This project will develop a behavioral drug discrimination paradigm for laboratory use with humans and will use this paradigm to evaluate comparatively the discriminative stimulus characteristics and the subjective, physiological, and behavioral effects of opioid agonists, antagonists and mixed agonist-antagonists in nondependent and in methadone-dependent human volunteers. Animal laboratory data suggest that opioids acting at different receptor sites (e.g., mu receptors vs. kappa and/or sigma receptors) possess distinctive discriminative stimulus characteristics which permit drug discrimination procedures to differentiate opioids with respect to their pharmacological profiles of action. In a residential human experimental laboratory volunteers will be trained to discriminate between the effects of two active drugs and saline administered intramuscularly. Following acquisition of this three-choice discrimination, various doses of the training drugs and/or other test drugs will be tested for similarity to the training drugs. Data analyses will compare discriminative performances as well as subjective, behavioral and physiological data collected in each session. In one series of studies, methadone-maintained subjects will be trained to discriminate between hydromorphone, naloxone and saline (a mu agonist vs. antagonist discrimination); comparative dose-effect functions will then be generated for the training drugs and for the mixed agonist-antagonists buprenorphine, pentazocine, butorphanol, and nalbuphine. In a second series of studies, nondependent postaddict volunteers will be trained to discriminate between hydromorphone, pentazocine and saline (a mu agonist vs. kappa/sigma agonist discrimination); comparative dose-effect functions will then be generated for the training drugs and for the mixed agonist-antagonists buprenorphine, butorphanol, nalbuphine and dezocine. One experiment will test for differential naloxone blockade of mu vs. kappa activity. Specificity of the discriminations will be assessed by testing with a range of nonopioids. Control experiments will assess the role of the specific training and testing procedures, including the role of explicit behavioral reinforcement contingencies. This paradigm will provide multifaceted comparative data concerning the discriminative stimulus characteristics and the subjective, behavioral and physiological effects of opioids -- especially mixed agonist-antagonist opioids -- and may prove valuable for study of opioid clinical pharmacology.